Description of the condition
Rheumatoid arthritis is a chronic systemic inflammatory disorder primarily affecting the synovial membrane. This inflammatory process leads to painful swelling of the joints due to the excess production of synovial fluid and fibrous tissue formation, which eventually results in bone erosion and joint deformity (Kvien 2005). Rheumatoid arthritis affects around 1% of the population in the world and it affects women more commonly than men in the age group of 40 to 60 years old (Silman 1998). Goals of the treatment are to reduce the disease activity, improve physical function, improve health-related quality of life, and to inhibit progression of structural damage throughout the course of the disease (Fries 1996). Treatment is primarily focused on disease modifying anti-rheumatic drugs (DMARDs), which are administered either orally, intravenously or by injection.
Description of the intervention
Tofacitinib was developed as a small molecule inhibitor of the Janus kinase (JAK) pathways that are central to the maintenance of the inflammatory state in rheumatoid arthritis (Regens 2011). The JAK family of kinases play a key role in cytokine induced signal transduction. Tofacitinib is highly specific for the JAK family of kinases over the other kinases. By inhibiting the activity of JAKs, tofacitinib reduces the production and modulates the effects of the key pro-inflammatory cytokines whose dysregulation is critical to immune cell activation, pro-inflammatory cytokine production and cytokine signalling. Tofacitinib is orally administered, usually in the dose range of 5 mg to 15 mg twice a day and has a half-life of two to five hours (Yamaoka 2012). The most common adverse effects are headache, nausea, and elevations in transaminase and creatinine levels (Fleischmann 2012). In a dose-dependent manner it increases the total cholesterol, high- and low-density lipoprotein levels and causes anemia and neutropenia in patients treated with doses of 30 mg twice a day; which suggest that this drug acts on the hematopoietic system through the pathway of JAK-2 inhibition (Zerbini 2012).
How the intervention might work
Tofacitinib selectively inhibits JAK-1, JAK-2 and JAK-3 in vitro, reducing the production of key pro-inflammatory cytokines which play a central role in the pathology of rheumatoid arthritis (Tanaka 2012). In recent randomized controlled trials, tofacitinib demonstrated rapid, significant, and clinically meaningful reductions in the disease activity score and improvements in physical function (Coombs 2010).
Why it is important to do this review
Although multiple DMARDs are available to treat rheumatoid arthritis, and combination therapy is frequently employed, many patients remain inadequately treated and continue to suffer pain, disability and progressive joint damage. Up to one third of patients do not adequately respond and about half stop responding to any particular DMARD within five years (Saag 2008). Since 1998, nine biologic agents have been approved by the US Food and Drug Administration (FDA) to treat moderate to severe rheumatoid arthritis that has not responded to an adequate trial of one or more of the traditional DMARDs. However, biologic DMARDs are expensive and due to the duration and chronic nature of the disease, patients can expect to require treatment for up to 40 years over their lifetime. A high likelihood that a patient will stop responding to any particular therapy means that many patients will exhaust available treatment options during the course of their disease. Thus, exploring additional therapeutic options with different mechanisms of action remains necessary to treat patients with moderate to severe disease. Tofacitinib is a targeted immune modulator that is being investigated for patients with rheumatoid arthritis. Compared with the newer therapeutic options, tofacitinib may have two advantages: (i) it can be orally administered and (ii) it is less costly (Bonilla-Hernan 2011). In this review, we will summarize the available evidence on the benefits and harms of tofacitinib. A systematic review may help clinicians in the decision-making process and in the implementation of the evidence into clinical practice.